Parkinson's disease (PD) is the most common movement disorder, affecting approximately 5 million people worldwide. PD is characterized by the clinical triad of resting tremor, rigidity and bradykinesia. The neuropathological hallmarks of PD are progressive degeneration of neurons in the substantia nigra and the presence of intraneuronal cytoplasmic inclusions known as Lewy bodies. Mutations in the LRRK2 and ?-synuclein genes are the most common genetic cause of PD, but the mechanisms underlying these mutations are still unclear. Emerging experimental evidence suggests intriguing common pathogenic mechanisms between these two dominant PD genes. For example, LRRK2 is an essential regulator of the autophagy-lysosomal pathway, of which ?-synuclein is a substrate. Disruption of this pathway may explain DA neurodegeneration in PD, as impaired autophagy function caused by conditional deletion of genes encoding autophagy-related proteins leads to neurodegeneration during aging. However, how LRRK2 regulates autophagy and whether PD mutations affect its role in autophagy regulation remain to be elucidated. Furthermore, ?-synuclein aggregation, a neuropathological hallmark of PD, causes neurodegeneration during aging, but the mechanisms underlying its neurotoxicity need to be explored further. To address these questions, we propose three inter-related, complementary Research Projects and one Research Core. Project 1 directed by Dr. Sdhof proposes to elucidate the mechanisms of ?-synuclein neurotoxicity in mouse and human neurons. Project 2, directed by Dr. Shen, proposes to investigate the genetic interaction between ?-synuclein and LRRK in the regulation of autophagy and dopaminergic neuron survival. Project 3, directed by Dr. Yue, proposes to investigate the molecular pathways by which LRRK regulates autophagy and ?-synuclein homeostasis. The Research Core, directed by Dr. Shen, will serve all three Projects by generating and providing multiple lines of mutant mice that are essential for the three Projects. The Administrative Core, also directed by Dr. Shen, will oversee the overall function and integration of our Udall Center, scientific directions of all Projects and Core, budget allocation, and our extensive training and public outreach programs. The completion of these highly integrated, complementary Projects and Research Core will provide significant insight into PD pathogenesis, and help uncover novel pathways that can be further explored and developed into effective disease-modifying therapy.